1. Field of the Invention
The present invention relates to a phytoestrogenic composition for preventing or treating symptoms associated with menopause.
2. Background of Technique
A hormone secreted from follicles in ovaries, estrogen, develops sexual organs and makes them functional to exhibit the secondary sexual character and accelerate the development of uterus, the growth of endometrium, the development of mammary gland and regular menstruation. In addition to ovaries, estrogen is secreted from placenta, adrenal cortex and testis in a small amount. Three types of steroids, estrone, estradiol and estriol found in body are known.
Estrogen is produced from androgenic precursors through an enzymatic process, aromatization. 17 beta-estradiol (E2), the most potent estrogen, which exists predominantly in premenopausal women is synthesized during the formation of ovarian follicles, is secreted into blood stream and bound to sex hormone binding globulin in a portion, and then circulates to cells in the body. The main metabolic pathway of estradiol is to be oxidized reversibly to estrone (E1), a weaker estrogen and finally converted to estriol (E3). Estrone is also produced by aromatization of androstenedione, a precursor of androgen, in the peripheral tissue. The above compounds are metabolized to form sulfate and glucuronide and excreted (Lievertz RW. Pharmacology and pharmacokinetics of estrogen. Am J Obstet Gynecol 156: 1289-1293 (1987)). As aromatization occurs in adipose tissue, those who have many adipose tissues have more estrogen. Estradiol and estrone may be metabolized in liver to estriol, very weak estrogen (Anderson F. Kinetics and pharmacology of estrogens in pre- and postmenopausal women. Int J Fertil 38 (suppl 1): 53-64 (1993)). Other estrogen metabolites as well as estradiol and estrone could function like estrogen. Therefore, it could be understood that the systematic estrogen effects in women depends on both estrogen and its metabolites.
The peak concentrations of estradiol and estrone are 200-400 pg/ml and 170-200 pg/ml in late follicular phase and decrease to the minimum concentration of 40-60 pg/ml in common during the early follicular phase.
The ratio of estradiol to estrone before menopause is generally lager than 1 (Odonnell M B. Pharmacokinetic and pharmacologic variation between different estrogen products. J Clin Pharmacol 35 (suppl): 18S-24S (1995)). After menopause, estrone produced by conversion of adrenal androstenedione becomes the predominant estrogen.
The metabolic pathway including 2-hydroxyation is more complicated and results in the formation of catecholesterogens. This pathway is more important in the central nervous system such as brain than in the peripheral tissue. Estrogen exhibits its effects by modifying catecholamine metabolism (Lievertz R W. Pharmacology and pharmacokinetics of estrogen. Am J Obstet Gynecol 156: 1289-1293 (1987)). Since catecholamine interacts with dophamin (a precursor of adrenalin) receptor, alpha 1-adrenalin receptor and serotonin receptor, it is considered to be important. Furthermore, the hydroxy derivatives of estrogen play other roles. For example, 4-hydroxy estrogen has estrogenic activity while 2-hydroxy estrogen does not. However, the 2-hydroxy derivatives of estradiol have not only estrogenic but also catecholaminergic activity (Lievertz R W. Pharmacology and pharmacokinetics of estrogen. Am J Obstet Gynecol 156: 1289-1293 (1987)). This accounts partially for the mechanism by which estrogens have an effect on the central nervous system.
The main physiological function of estrogen is to regulate the growth, differentiation and function of many reproductive tissues including mammary gland, uterus and ovary (Kuiper G G J M, Carlsson B, Grandien K, et al. Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta. Endocrinology 138: 863-870 (1997)). Estrogen stimulates the growth of endometrium, myometrium, vagina and urethral epithelium. In addition, estrogen enhances vascular flow in the genital tract, increases secretion of cervical gland, and induces the expression of progesterone and luteinzing hormone receptors. Estrogen has an effect on the growth and development of backbone, fat distribution in women in addition to developing the female reproductive organs and secondary sex characteristics at puberty. Estrogen plays roles in skin, collagen tissue, neuron and cardiovascular system.
Estrogen deficiency brings up the symptoms such as hot flashes caused by vasomotor instability and in the long term, urogenital atrophy, osteoporosis, tooth loss, arteriosclerosis and coronary heart disease, and potentially, increases the risk of dementia (Maddox R W, Carson D S, Barnes C L. Estrogens and postmenopausal women. U S Pharmacist 23: 141-150 (1998); and Guyton A C, Hall J E. Textbook of Medical Physiology. 9th ed. Philadelphia: W.B. Saunders, 1996).
After menopause, when ovarian function declines, women experience a state of estrogen deficiency causing various menopausal symptoms such as facial flushing, depression, etc. Hormone replacement therapy is recommended for some women to alleviate menopausal symptoms of estrogen deficiency and to minimize the potential long-term health consequences of estrogen deficiency.
Administering estrogen into postmenopausal women improves vasomotion and urogenital diseases, protects and controls osteoporosis and reduces the risk of coronary heart disease (Maddox R W, Carson D S, Barnes C L. Estrogens and postmenopausal women. US Pharmacist 23: 141-150 (1998)).
However, the problem is that such a hormone replacement therapy may increase the activity of cancer-inducing gene, leading to increased incidence rate of cancers such as breast cancer and endometrial cancer.
The known estrogen-replacing agents are artificially synthesized or available from natural source. For example, Premarin is made from pregnant horse's urine with the increased concentration of estradiol and estrone up to that in secretion phase (Stumpf P G. Pharmacokinetics of estrogen. Obstet Gynecol 75 (suppl): 9S-14S (1990)). However, it has been reported during several decades that the estrogen replacement therapy results in serious side effects. A multi-center randomized double-blind clinical test (Women's Health Initiative (WHI)) would be planned with some 16,000 postmenopausal women for 8 years, but was terminated earlier in 5 years due to serious adverse events. In result, FDA forced all the HRT products to have black warning label in 2003. According to WHI, HRT increased the number of cases with breast cancer by 26%, heart disease by 29%, and stroke by 44%. Blood clot rates were more than twice as high as in those getting HRT (Journal of the American Medical Association, July 2002). NAMS (North America Menopause Society) strongly recommends that “the use of hormone combination therapy has to be prohibited for primary or secondary prophylaxis of cardiovascular diseases” and “it is not desirable to use the only estrogen therapy unless firm research data are deduced”.
On the other hand, such plants as soy bean, date palm and pomegranate contain non-steroid plant compounds, phytoestrogen. Natural phytoestrogen originated from these plant functions as agonists and/or antagonist (Barrett J. Phytoestrogens: friends or foes? Environ Health Perspect 104: 478-482 (1996)).
Additionally, 17 beta-estradiol, estrone, estrogen sulfate are the examples of chemically modified estrogen. Such synthesized estrogen is used generally as an oral contraceptive, but hardly in hormone replacement therapy.
In short, the amount of estrogen secreted decreases with aging and the pattern of estrogen secretion is directly related to the advancement of aging. It has been recognized in the art that the administration of hormone replacement therapy allows to improve the usual symptoms of menopause, while the conventional hormone replacement therapy gives rise to severe adverse effects.
Throughout this application, various publications and patents are referred and citations are provided in parentheses. The disclosure of these publications and patents in their entities are hereby incorporated by references into this application in order to fully describe this invention and the state of the art to which this invention pertains.